Aging of the population and the increased prevalence of chronic diseases among the elderly are major challenges facing our society and medical community. More than 20% of Americans will experience an episode of depression serious enough to warrant diagnosis and treatment. Treatment of major depressive disorder (MDD) has focused on reduction of symptoms and restoration of functioning. Although antidepressant medication has been particularly effective in this regard, many patients either fail to respond to medication or suffer from significant side effects. Thus, there continues to be a need to identify alternative approaches for treating depression, particularly in the elderly. There is now good reason to believe that exercise may be one such approach. The study proposed in the application will build upon the applicant's previous work in which they demonstrated the feasibility and efficacy of exercise as a treatment for MDD in older men and women. The major aim of this project will be to test the hypothesis that a program of home exercise is as effective as supervised exercise and medication in reducing depression relative to placebo controls. As a further extension of past work, the Principal Investigator proposes to examine the differential effectiveness of exercise for a significant subgroup of patients identified by Magnetic Resonance Imaging of the brain as having "vascular depression." Two hundred sixteen men and women, aged > 55 years, with MDD will be randomly assigned to supervised exercise, home exercise, drug (sertraline), or placebo. Before and after treatment patients will undergo evaluation of depression and exercise testing, assessment of vascular functioning including endothelial dysfunction and baroreceptor control, and psychometric testing to assess cognitive function and other measures of quality of life. Six month follow-up will assess relapse rates. The data generated from this study will have important practical implications by determining the extent to which exercise may benefit older men and women with MDD. The study also will provide information regarding the relationship between vascular depression and various indices of vascular and neurocognitive function, and the extent to which these indices may be modifiable by treatment.